The Influence of Body Mass Index on Clinical Interpretation of Established and Novel Biomarkers in Acute Heart Failure.

BACKGROUND: Body mass index (BMI) is a known confounder for natriuretic peptides, but its influence on other biomarkers is less well described. We investigated whether BMI interacts with biomarkers' association with prognosis in patients with acute heart failure (AHF). METHODS AND RESULTS: B-type natriuretic peptide (BNP), high-sensitivity cardiac troponin I (hs-cTnI), galectin-3, serum neutrophil gelatinase-associated lipocalin (sNGAL), and urine NGAL were measured serially in patients with AHF during hospitalization in the AKINESIS (Acute Kidney Injury Neutrophil gelatinase-associated lipocalin Evaluation of Symptomatic Heart Failure) study. Cox regression analysis was used to determine the association of biomarkers and their interaction with BMI for 30-day, 90-day and 1-year composite outcomes of death or HF readmission. Among 866 patients, 21.2%, 29.7% and 46.8% had normal (18.5-24.9 kg/m2), overweight (25-29.9 kg/m2) or obese (≥ 30 kg/m2) BMIs on admission, respectively. Admission values of BNP and hs-cTnI were negatively associated with BMI, whereas galectin-3 and sNGAL were positively associated with BMI. Admission BNP and hs-cTnI levels were associated with the composite outcome within 30 days, 90 days and 1 year. Only BNP had a significant interaction with BMI. When BNP was analyzed by BMI category, its association with the composite outcome attenuated at higher BMIs and was no longer significant in obese individuals. Findings were similar when evaluated by the last-measured biomarkers and BMIs. CONCLUSIONS: In patients with AHF, only BNP had a significant interaction with BMI for the outcomes, with its association attenuating as BMI increased; hs-cTnI was prognostic, regardless of BMI.

Galectin-3, Acute Kidney Injury and Myocardial Damage in Patients With Acute Heart Failure.

BACKGROUND: Galectin-3, a biomarker of inflammation and fibrosis, can be associated with renal and myocardial damage and dysfunction in patients with acute heart failure (AHF). METHODS AND RESULTS: We retrospectively analyzed 790 patients with AHF who were enrolled in the AKINESIS study. During hospitalization, patients with galectin-3 elevation (> 25.9 ng/mL) on admission more commonly had acute kidney injury (assessed by KDIGO criteria), renal tubular damage (peak urine neutrophil gelatinase-associated lipocalin [uNGAL] > 150 ng/dL) and myocardial injury (≥ 20% increase in the peak high-sensitivity cardiac troponin I [hs-cTnI] values compared to admission). They less commonly had ≥ 30% reduction in B-type natriuretic peptide from admission to last measured value. In multivariable linear regression analysis, galectin-3 was negatively associated with estimated glomerular filtration rate and positively associated with uNGAL and hs-cTnI. Higher galectin-3 was associated with renal replacement therapy, inotrope use and mortality during hospitalization. In univariable Cox regression analysis, higher galectin-3 was associated with increased risk for the composite of death or rehospitalization due to HF and death alone at 1 year. After multivariable adjustment, higher galectin-3 levels were associated only with death. CONCLUSIONS: In patients with AHF, higher galectin-3 values were associated with renal dysfunction, renal tubular damage and myocardial injury, and they predicted worse outcomes.

Floral and pollination characteristics of Eriocaulon heleocharioides, an extinct species in the wild, for evidence-based conservation management.

Generally, floral characteristics and pollination are important factors enhancing the quality and quantity of reproductive output for regeneration in plant conservation. However, lack of evidence-based management could decrease fitness under ex-situ conservation. We investigated the capitulum and pollination characteristics of Eriocaulon heleocharioides Satake (Eriocaulaceae), which is extinct in the wild, to develop an evidence-based conservation management plan incorporating previously ignored reproductive characteristics. To evaluate the functional characteristics of capitula, pollen-ovule ratio, and reproductive status (maximum pollination success/florivory damage) were investigated along six flowering sequences of capitulum. To evaluate the effect of plant density on pollen transfer, high- and low-density plots were established. Total deposited pollen on stigma, insect visitation, and visit duration per capitulum were observed. A significantly lower pollen-ovule ratio was observed in the first of six capitula, reflecting higher female functionality. The highest pollination success was found in the second-fourth capitula, whereas florivory increased along the terminal capitula position. High plant density affected the pollen deposited on stigmas via insect visitation and low pollinator visit duration. Different capitula in E. heleocharioides could have different effects: different sexual functionality, enhancement of reproductive output both in quality and quantity through active pollen transfer, and escaping from florivores. High plant density could facilitate outcross-pollen transfer in E. heleocharioides. Multiple perspectives are important for determining potential reproductive success in ex-situ conservation. Thus, density management reflecting capitulum characteristics could improve the efficiency of conservation efforts for E. heleocharioides.

Potential Utility of Cardiorenal Biomarkers for Prediction and Prognostication of Worsening Renal Function in Acute Heart Failure.

BACKGROUND: Multiple different pathophysiologic processes can contribute to worsening renal function (WRF) in acute heart failure. METHODS AND RESULTS: We retrospectively analyzed 787 patients with acute heart failure for the relationship between changes in serum creatinine and biomarkers including brain natriuretic peptide, high sensitivity cardiac troponin I, galectin 3, serum neutrophil gelatinase-associated lipocalin, and urine neutrophil gelatinase-associated lipocalin. WRF was defined as an increase of greater than or equal to 0.3 mg/dL or 50% in creatinine within first 5 days of hospitalization. WRF was observed in 25% of patients. Changes in biomarkers and creatinine were poorly correlated (r ≤ 0.21) and no biomarker predicted WRF better than creatinine. In the multivariable Cox analysis, brain natriuretic peptide and high sensitivity cardiac troponin I, but not WRF, were significantly associated with the 1-year composite of death or heart failure hospitalization. WRF with an increasing urine neutrophil gelatinase-associated lipocalin predicted an increased risk of heart failure hospitalization. CONCLUSIONS: Biomarkers were not able to predict WRF better than creatinine. The 1-year outcomes were associated with biomarkers of cardiac stress and injury but not with WRF, whereas a kidney injury biomarker may prognosticate WRF for heart failure hospitalization.

Identification of an argpyrimidine-modified protein in human red blood cells from schizophrenic patients: A possible biomarker for diseases involving carbonyl stress.

Argpyrimidine (ARP) is an advanced glycation end product thought to be generated from a reaction between methylglyoxal and arginine residues in proteins. In this study, we observed marked accumulation of an approximately 56 kD protein, reactive to anti-ARP antibodies, in the red blood cells (RBCs) of some patients with refractory schizophrenia. This ARP-modified protein was purified from the blood of schizophrenic patients and identified as selenium binding protein 1 (SBP1) by LC-MS/MS. This is the first report of ARP-modified proteins accumulating in RBCs of patients with diseases involving carbonyl stress. We also observed high accumulation of ARP-modified SBP1 in the RBCs of patients with chronic kidney disease. Therefore, this modified protein may be a novel marker of carbonyl stress.

Molecular signatures associated with cognitive deficits in schizophrenia: a study of biopsied olfactory neural epithelium.

Cognitive impairment is a key feature of schizophrenia (SZ) and determines functional outcome. Nonetheless, molecular signatures in neuronal tissues that associate with deficits are not well understood. We conducted nasal biopsy to obtain olfactory epithelium from patients with SZ and control subjects. The neural layers from the biopsied epithelium were enriched by laser-captured microdissection. We then performed an unbiased microarray expression study and implemented a systematic neuropsychological assessment on the same participants. The differentially regulated genes in SZ were further filtered based on correlation with neuropsychological traits. This strategy identified the SMAD 5 gene, and real-time quantitative PCR analysis also supports downregulation of the SMAD pathway in SZ. The SMAD pathway has been important in multiple tissues, including the role for neurodevelopment and bone formation. Here the involvement of the pathway in adult brain function is suggested. This exploratory study establishes a strategy to better identify neuronal molecular signatures that are potentially associated with mental illness and cognitive deficits. We propose that the SMAD pathway may be a novel target in addressing cognitive deficit of SZ in future studies.

Clinical utility of neuronal cells directly converted from fibroblasts of patients for neuropsychiatric disorders: studies of lysosomal storage diseases and channelopathy.

Methodologies for generating functional neuronal cells directly from human fibroblasts [induced neuronal (iN) cells] have been recently developed, but the research so far has only focused on technical refinements or recapitulation of known pathological phenotypes. A critical question is whether this novel technology will contribute to elucidation of novel disease mechanisms or evaluation of therapeutic strategies. Here we have addressed this question by studying Tay-Sachs disease, a representative lysosomal storage disease, and Dravet syndrome, a form of severe myoclonic epilepsy in infancy, using human iN cells with feature of immature postmitotic glutamatergic neuronal cells. In Tay-Sachs disease, we have successfully characterized canonical neuronal pathology, massive accumulation of GM2 ganglioside, and demonstrated the suitability of this novel cell culture for future drug screening. In Dravet syndrome, we have identified a novel functional phenotype that was not suggested by studies of classical mouse models and human autopsied brains. Taken together, the present study demonstrates that human iN cells are useful for translational neuroscience research to explore novel disease mechanisms and evaluate therapeutic compounds. In the future, research using human iN cells with well-characterized genomic landscape can be integrated into multidisciplinary patient-oriented research on neuropsychiatric disorders to address novel disease mechanisms and evaluate therapeutic strategies.

Ulnar nerve strain at the elbow in patients with cubital tunnel syndrome: effect of simple decompression.

Simple decompression of the ulnar nerve at the elbow has not been shown to reduce nerve strain in cadavers. In this study, ulnar nerve strain at the elbow was measured intraoperatively in 11 patients with cubital tunnel syndrome, before and after simple decompression. Statistical analysis was performed using a paired Student's t-test. Mean ulnar nerve strain before and after simple decompression was 30.5% (range 9% to 69%) and 5.5% (range -2% to 11%), respectively; this difference was statistically significant (p < 0.01) with a statistical power of 96%. Simple decompression reduced ulnar nerve strain in all patients by an average of 24.5%. Our results suggest that the pathophysiology of cubital tunnel syndrome may be multifactorial, being neither a simple compression neuropathy nor a simple traction neuropathy, and simple decompression may be a favourable surgical procedure for cubital tunnel syndrome in terms of decompression and reduction of strain in the ulnar nerve.

DPP6 as a candidate gene for neuroleptic-induced tardive dyskinesia.

We implemented a two-step approach to detect potential predictor gene variants for neuroleptic-induced tardive dyskinesia (TD) in schizophrenic subjects. First, we screened associations by using a genome-wide (Illumina HumanHapCNV370) SNP array in 61 Japanese schizophrenia patients with treatment-resistant TD and 61 Japanese schizophrenia patients without TD. Next, we performed a replication analysis in 36 treatment-resistant TD and 138 non-TD subjects. An association of an SNP in the DPP6 (dipeptidyl peptidase-like protein-6) gene, rs6977820, the most promising association identified by the screen, was significant in the replication sample (allelic P=0.008 in the replication sample, allelic P=4.6 × 10(-6), odds ratio 2.32 in the combined sample). The SNP is located in intron-1 of the DPP6 gene and the risk allele was associated with decreased DPP6 gene expression in the human postmortem prefrontal cortex. Chronic administration of haloperidol increased Dpp6 expression in mouse brains. DPP6 is an auxiliary subunit of Kv4 and regulates the properties of Kv4, which regulates the activity of dopaminergic neurons. The findings of this study indicate that an altered response of Kv4/DPP6 to long-term neuroleptic administration is involved in neuroleptic-induced TD.

The prevalence of dogs with lymphocyte proliferative responses to food allergens in canine allergic dermatitis.

The aim of the present study was to examine the correlation between the results of lymphocyte proliferative test (LPT) specific to food allergens and allergic skin diseases in dogs. Investigations were performed in 138 dogs with allergic skin diseases diagnosed in a private animal hospital. Of the 138 animals, 97 cases had positive reactions in LPT specific to food allergens. Of these 97 dogs, 67 animals were diagnosed with canine atopic dermatitis (CAD), but 30 dogs did not have IgE antibodies to environmental allergens. As 14 dogs out of 30 animals showed a positive result, 12 dogs underwent elimination diet trial based on the test results and all of them showed improvement in the pruritus score. Therefore, we conclude that LPT is an effective diagnostic test for allergic skin disease. Results of the lymphocyte test are useful in the identification of food allergens for the elimination diet trial.

Long-reach 10-Gb/s RSOA-based WDM PON employing QPSK signal and coherent receiver.

We demonstrate a long-reach wavelength-division-multiplexed passive optical network (WDM PON) operating at the symmetric rate of 10.3 Gb/s. For the cost-effectiveness, we realize the upstream transmission by utilizing directly-modulated TO-can packaged reflective semiconductor optical amplifiers (RSOAs) and digital coherent receivers. In addition, to overcome the limited modulation bandwidth of this TO-can packaged RSOA (~2.2 GHz) and operate it at 10.3 Gb/s, we utilize the quadrature phase shift keying (QPSK) format and the electronic phase equalization technique. The result shows that we can extend the maximum reach of the 10.3-Gb/s RSOA-based WDM PON to ~80 km without using any remote amplifiers.

Endoscopic mucosal resection and endoscopic submucosal dissection for en bloc resection of superficial pharyngeal carcinomas.

BACKGROUND AND STUDY AIM: Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) are being used increasingly to treat superficial oropharyngeal and hypopharyngeal carcinomas. The aim of this study was to clarify whether ESD provided better results than EMR for en bloc and complete resection of superficial pharyngeal carcinomas. PATIENTS AND METHODS: A total of 76 superficial pharyngeal carcinomas in 59 consecutively treated patients were included. Patients underwent either conventional EMR (using a transparent cap or strip biopsy) (n = 45 lesions) or ESD (n = 31 lesions) between October 2006 and January 2011. The rates of en bloc resection, complete resection (defined as en bloc resection with tumor-free margins), major complications, and local recurrence were evaluated retrospectively as the therapeutic outcomes. RESULTS: ESD yielded significantly higher rates of both en bloc and complete resection compared with EMR (en bloc 77.4 % [24/31] vs. 37.8 % [17/45], P = 0.0002; complete 54.8 % [17/31] vs. 28.9 % [13/45], P = 0.0379). ESD was more frequently complicated by severe laryngeal edema (4/21 [19.0 %] vs. 1/31 [3.2 %], P = 0.1446) and was also more time-consuming (124.9 ± 65.1 minutes vs. 57.2 ± 69.6 minutes; P = 0.0014). Local recurrence was observed more often after EMR than after ESD (3/45 [6.7 %] vs. 0/31 [0 %]), although this difference did not reach statistical significance (P = 0.2658). CONCLUSIONS: ESD appears to be a superior method of endoscopic resection of superficial pharyngeal carcinomas for achieving both en bloc and complete resection, although these benefits were also associated with a higher incidence of complications and a significantly longer procedure time. Large prospective studies are needed to compare ESD with conventional EMR for superficial pharyngeal carcinomas.

Urokinase-type plasminogen activator and plasminogen mediate activation of macrophage phagocytosis during liver repair in vivo.

Urokinase-type plasminogen activator (u-PA) and plasminogen play a primary role in liver repair through the accumulation of macrophages and alteration of their phenotype. However, it is still unclear whether u-PA and plasminogen mediate the activation of macrophage phagocytosis during liver repair. Herein, we investigated the morphological changes in macrophages that accumulated at the edge of damaged tissue induced by a photochemical reaction or hepatic ischaemia-reperfusion in mice with u-PA ( u-PA-/- ) or plasminogen ( Plg-/- ) gene deficiency by using transmission electron and fluorescence microscopy. In wild-type mice, the macrophages aligned at the edge of the damaged tissue and extended a large number of long pseudopodia. These macrophages clearly engulfed cellular debris and showed well-developed organelles, including lysosome-like vacuoles, nuclei, and Golgi complexes. In wild-type mice, the distribution of the Golgi complex in these macrophages was biased towards the direction of the damaged tissue, indicating the extension of their pseudopodia in this direction. Conversely, in u-PA-/- and Plg-/- mice, the macrophages located at the edge of the damaged tissue had few pseudopodia and less developed organelles. The Golgi complex was randomly distributed in these macrophages in u-PA-/- mice. Furthermore, interferon γ and IL-4 were expressed at a low level at the border region of the damaged tissue in u-PA-/- mice. Our data provide novel evidence that u-PA and plasminogen are essential for the phagocytosis of cellular debris by macrophages during liver repair. Furthermore, u-PA plays a critical role in the induction of macrophage polarity by affecting the microenvironment at the edge of damaged tissue.

Usefulness of MRA-DWI mismatch in neuroendovascular therapy for acute cerebral infarction.

BACKGROUND: This study evaluated the usefulness of MR angiography (MRA)-diffusion-weighted imaging (DWI) mismatch in neuroendovascular therapy over 3 h after onset of acute cerebral infarction. METHODS: The subjects were 14 cases (age, 73 ± 8.4 years) who had an anterior circulation deficit on DWI/MRA on arrival and underwent neuroendovascular therapy over 3 h after onset. MRA-DWI mismatch (MDM) (+) was defined as 'major artery lesion (+) and diffusion-weighted image-Alberta Stroke Program Early CT Score (DWI-ASPECTS) ≥6'; MDM (-) was defined as 'major artery lesion (+) and DWI-ASPECTS <6'. RESULTS: Reperfusion was achieved in nine of 14 patients (64%) undergoing neuroendovascular therapy. Within the reperfusion group, in the five MDM (+) patients and the four MDM (-) patients, the outcome was a favorable clinical response in the MDM (+) group. The modified Rankin Scale (mRS) scores after 90 days were 0-2 in 3 (60%) and 3-6 in 2 (40%) of the MDM (+) group patients and 0-2 in 0 (0%) and 3-6 in 4 (100%) of the MDM (-) group patients. In the MDM (+) group, a good outcome was achieved. However, the number of cases was small, so this was not a significant difference. Within the non-reperfusion group, in the three MDM (+) patients and the two MDM (-) patients, the mRS scores after 90 days were 0-2 in 1 (33%) and 3-6 in 2 (67%) of the MDM (+) group patients and 0-2 in 0 (0%) and 3-6 in 2 (100%) of the MDM (-) group patients. In both groups, the outcome was poor. CONCLUSIONS: With neuroendovascular therapy, a good outcome with reperfusion was achieved in the MDM (+) group compared to the MDM (-) group. This suggests that the presence or absence of MDM may be useful in determining prognosis after reperfusion.

Surgical treatment of spontaneous posterior interosseous nerve palsy: a retrospective study of 50 cases.

We have reviewed 38 surgically treated cases of spontaneous posterior interosseous nerve palsy in 38 patients with a mean age of 43 years (13 to 68) in order to identify clinical factors associated with its prognosis. Interfascicular neurolysis was performed at a mean of 13 months (1 to 187) after the onset of symptoms. The mean follow-up was 21 months (5.5 to 221). Medical Research Council muscle power of more than grade 4 was considered to be a good result. A further 12 cases in ten patients were treated conservatively and assessed similarly. Of the 30 cases treated surgically with available outcome data, the result of interfascicular neurolysis was significantly better in patients < 50 years old (younger group (18 nerves); good: 13 nerves (72%), poor: five nerves (28%)) than in cases > 50 years old (older group (12 nerves); good: one nerve (8%), poor: 11 nerves (92%)) (p < 0.001). A pre-operative period of less than seven months was also associated with a good result in the younger group (p = 0.01). The older group had a poor result regardless of the pre-operative delay. Our recommended therapeutic approach therefore is to perform interfascicular neurolysis if the patient is < 50 years of age, and the pre-operative delay is < seven months. If the patient is > 50 years of age with no sign of recovery for seven months, or in the younger group with a pre-operative delay of more than a year, we advise interfascicular neurolysis together with tendon transfer as the primary surgical procedure.

Diversity of molecular forms of plasma brain natriuretic peptide in heart failure--different proBNP-108 to BNP-32 ratios in atrial and ventricular overload.

OBJECTIVE: Recent studies have shown that plasma levels of brain natriuretic peptide (BNP)-32 and proBNP-108 are increased in heart failure (HF) and that the BNP-32 assay kit in current clinical use cross-reacts with proBNP-108. We investigated why proBNP is increased without processing in HF was investigated. DESIGN, SETTING AND PATIENTS: Plasma BNP-32 and proBNP-108 in normal individuals (n=10) and in patients with atrial fibrillation (AF) (n=18) and HF (n=132) was measured. BNP-32 and proBNP-108 in ventricular and atrial tissue and in pericardial fluid using a specific fluorescent enzyme immunoassay following Sep-Pak C18 (Waters, Milford, Massachusetts, USA) cartridge extraction and gel filtration was also measured. MAIN OUTCOME MEASURES: Levels of both BNP-32 and proBNP-108 were higher in HF than in control or AF (both p<0.01), and the levels of these peptides significantly correlated (r=0.94, p<0.001). The proBNP-108/total BNP (BNP-32+proBNP-108) ratio was widely distributed and lower in HF (0.33 (0.17)) than in control (0.41 (0.06), p<0.05) and AF (0.45 (0.04), p<0.002). The proBNP-108/total BNP ratio was higher in HF with ventricular than in HF with atrial overload (0.45 (0.10) vs 0.20 (0.11), p<0.001). Consistent with this finding, the major molecular form were proBNP-108 and BNP-32 in ventricular (n=6, 0.67 (0.04)) and atrial (n=7, 0.76 (0.05), p<0.0001) tissues, respectively. ProBNP-108 was also the major molecular form of BNP in pericardial fluid (n=8, 0.82 (0.05)). The proBNP-108/total BNP ratio increased and decreased with HF deterioration and improvement, respectively. CONCLUSION: These results suggest that BNP-32 and proBNP-108 is increased in HF and that the proBNP/total BNP ratio increases in association with pathophysiological conditions such as ventricular overload.

A nonsynonymous polymorphism in cannabinoid CB2 receptor gene is associated with eating disorders in humans and food intake is modified in mice by its ligands.

Marijuana use activates cannabinoid receptors (CB-Rs) producing several behavioral effects related to addiction, mood, and appetite. We investigated the association between CNR2 gene, which encodes cannabinoid CB2 receptor (CB2-R) and eating disorders in 204 subjects with eating disorders and 1876 healthy volunteers in Japanese population. The effect of treatment with CB2-R ligands on mouse food consumption was also determined. The CB2-R ligands used suppressed food intake in a time- and strain-dependent manner when food was available ad libitum and during the 12-h fast except, AM 630-the CB2-R antagonist that stimulated food consumption in food-deprived mice. There is an association between the R63Q polymorphism of the CNR2 gene and eating disorders (P = 0.04; Odds ratio 1.24, 95% CI, (1.01-1.53). These results suggest that cannabinoid CB2-R is involved in the endocannabinoid signaling mechanisms associated with the regulation of food intake and in eating disorders.

Modified intra-cerebral challenge assay for acellular pertussis vaccines: comparisons among whole cell and acellular vaccines.

The modified intra-cerebral challenge assay for acellular pertussis vaccines is used in Japan, Korea, China and possibly other Asian countries as the potency assay for routine release of acellular pertussis (aP) and combination vaccines. National reference standards, typically of whole cell pertussis (Pw) vaccine, are in use in these countries, but there is no agreed international reference standard for acellular pertussis vaccines. We report here the results of a collaborative study initiated in September 2006 in which fourteen laboratories performing the modified intra-cerebral challenge assay took part. These laboratories compared their various national references of Pw vaccine, the third International Standard for whole cell pertussis vaccine, a previously studied two-component freeze-dried aP vaccine preparation coded JNIH-3, and four different aP vaccines in combination with diphtheria and tetanus toxoids. The results of this study show that the modified intra-cerebral challenge assay works reliably although there are inter-laboratory variations in potency estimates. Pw and aP vaccines show apparent differences in dose-response lines in some assay systems. This indicates dissimilarity in performance in at least some of these assay systems. Estimates of relative potency for aP vaccines in terms of the Pw vaccine national or in-house reference preparations differ significantly from one another. Different mouse strains were used in each country and the different strains may also differ in their responsiveness to Pw and aP vaccines. Estimates for different types of aP vaccine formulations show less inter-laboratory variation in terms of JNIH-3 than in terms of the third IS for Pw vaccine and the remaining variation is not apparently related to the different mouse strains. This study thus suggests that an aP vaccine standard would improve inter-laboratory agreement. These data do not show significant dissimilarity in dose-response lines between JNIH-3 and the various vaccine products included, irrespective of the differences in aP components. Available data indicate that JNIH-3 is sufficiently stable to serve as an International Standard. On the basis of these results and with the agreement of the participants, it was proposed that JNIH-3 should be established as an International Standard for acellular pertussis vaccine for use in the modified intra-cerebral challenge assay and other protective bioassays, with an assigned activity of 34 International Units (IU) per ampoule. A WHO Working Group on Standardization of Acellular Pertussis Vaccines: potency assay met in Beijing, China, 7-9 November 2007. This group considered the report of this study, the comments of the participants and implications of the use of JNIH-3 as a reference standard and recommended establishment of JNIH-3 as an International Standard. The results of this study and the report of the Working Group were submitted to the Expert Committee on Biological Standardization (ECBS) of WHO which established JNIH-3 as the first International Standard for acellular pertussis vaccine in the modified intra-cerebral challenge assay and other protective bioassays with an assignment of 34IU per ampoule in October 2008.

Association of polymorphisms in the haplotype block spanning the alternatively spliced exons of the NTNG1 gene at 1p13.3 with schizophrenia in Japanese populations.

Chromosome 1p13 is linked with schizophrenia in Japanese families, and one of the candidate genes in this region is the netrin G1 (NTNG1) gene at 1p13.3. Associations of 56 tag single-nucleotide polymorphisms (SNPs) with schizophrenia were explored by transmission disequilibrium analysis in 160 Japanese trios and by case-control analysis in 2,174 Japanese cases and 2,054 Japanese controls. An association between SNP rs628117 and schizophrenia was identified by case-control comparison (nominal allelic p=0.0009; corrected p=0.006). The associated polymorphism is located in intron 9 and in the haplotype block encompassing the alternatively spliced exons of the gene. Allelic association of a different SNP in the same haplotype block in Japanese families was previously reported. These findings support that the NTNG1 gene is associated with schizophrenia in the Japanese.